Fungal infections are clinically common and frequently-occurring diseases. Said infections can be classified into superficial fungal infections and deep fungal infections. The superficial infections are caused by fungi invading skin, hair, finger (toe), and other body surface parts, and have high incidence and less harmful effects. Deep fungal infections are caused by Candida, Aspergillus, Cryptococcus and other fungi invading internal organs and deep tissues, and are of great harm.
In recent years, with the increasing number of immunosuppressed patients, the incidence of deep fungal infections has increased significantly. Fungal infections, especially deep fungal infections, are increasingly attracting widespread attention. However, at present, clinically applied antifungal drugs have serious side effects and are susceptible to drug resistance. Clinically existing antifungal drugs can be divided into organic acids, polyenes, azoles, allylamines, etc. according to their structures. Among them, azole antifungal drugs are a class of rapidly developing fully synthetic antifungal compounds. Currently, it has become the main medication for the treatment of deep and superficial fungal infections. Since the first anti-fungal effect of the first azole compound was reported in the middle of the last century, the first generation of triazoles such as fluconazole, itraconazole, and the second generation of triazole voriconazole gradually appeared in the field of antifungal treatment.
Posaconazole is a derivative of itraconazole. Its oral suspension was first marketed in Germany in 2005 and was approved by the FDA in 2006. It is clinically effective in treating systemic fungal infections caused by Aspergillus and Candida as well as oropharyngeal candidiasis. Posaconazole is currently approved in more than 70 countries and regions around the world, and is listed in more than 40 countries and regions including the United States and the European Union. However, the degree of absorption of oral suspensions is easily affected by factors such as food and gastrointestinal function, leading to large differences in pharmacokinetic parameters among individuals, fluctuations in blood drug concentration range, lower bioavailability and other issues. Posaconazole is a weakly alkaline, poorly water-soluble drug and is not easily developed into an injection form. Some immunosuppressed patients undergoing chemotherapy or organ transplantation have problems such as nausea, vomiting, and gastrointestinal discomfort, resulting in difficulty in oral administration and need to be administered by injection.
In order to solve the problem that posaconazole is difficult to develop into an injection preparation due to poor solubility, Patent Application No. 201180031488.9 of Merck Sharp & Dohme Ltd. discloses a formulation of intravenous infusion of poraconazole that is solubilized with substituted β-cyclodextrin, and an injectable formulation is prepared by solubilizing posaconazole with a substituted β-cyclodextrin in which an injectable formulation is prepared by solubilizing posaconazole with substituted β-cyclodextrin. The injection is currently approved for listing in the United States. Although the injection solves the problem that posaconazole is insoluble in water and achieves administration to patients who are inconvenient for oral administration, due to the addition of a large amount of sulfobutyl ether-β-cyclodextrin (SBE-β-CD) for solubilization, there is a potential safety risk, and preclinical toxicology studies have shown that sulfobutyl ether-β-cyclodextrin causes vacuolization of urethral epithelial cells and activates liver and lung macrophages. Clinical studies have shown that SBE-β-CD needs to be metabolized through the kidneys, which greatly increases the burden on the kidneys. The target patients for posaconazole injections are patients who have undergone bone marrow transplantation, chemotherapy, and other immunosuppression and fungal infections. Renal impairment is present in a significant proportion of patients, particularly in patients with moderate or severe renal insufficiency having lower glomerular filtration efficiency, resulting in accumulation of SBE-β-CD in the body with high safety risks. The use of excipient sulfobutyl ether-β-cyclodextrin greatly limits the clinical application of the drug. The instruction for posaconazole injection specifically states that the drug is not suitable for patients with moderate to severe renal impairment. Therefore, it is of great clinical value to improve the existing deficiencies in the prior art and increase the safety and drug applicability for renal injury patients.
Contents of the Present Disclosure
The present disclosure provides a compound represented by the following formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof:

wherein, R is selected from unsubstituted or optionally substituted triazole groups, for example, from the following groups which are unsubstituted or optionally substituted with one or more Ra or Rb:

Rt is selected from

X1 and X2 are independently selected from F, Cl, Br, or I;
Each X3 is independently selected from pharmaceutically acceptable anions;
R1 is selected from OH or Rh; Rh is a group that can be converted into a hydroxyl group in vivo, for example,
O(O)CRf, —OP(O)(OM1)(OM2), —OS(O)2OM3, or the following groups which are unsubstituted or optionally substituted with one or more Rb: C1-40 alkyloxy, C3-20 cycloalkyloxy, 3-20 membered heterocyclyloxy, C6-20 aryloxy, or 5-20 membered heteroaryloxy;
R2 and R4 are independently selected from H, or C1-40 alkyl which is unsubstituted or optionally substituted with one or more Ra;
R3 is selected from C1-40 alkyl which is unsubstituted or optionally substituted with one or more Rb;
R5 and R6 are independently selected from H, or the following groups which are unsubstituted or optionally substituted with one or more Rm: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, or —C(O)Rf;
Ar is selected from the following groups which are unsubstituted or optionally substituted with one or more Rc: C6-20 aryl, 5-20 membered heteroaryl, wherein the heteroaryl comprises 1-5 heteroatoms independently selected from N, O, and S;
R7 is selected from the following groups which are unsubstituted or optionally substituted with one or more Rc: C1-40 alkyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, —Y2P(O)(OM1)(OM2), —C(O)Rf or —(CH2CH2O)z—Rb, wherein z is an integer of 1 or more, preferably an integer of 1 to 10;
R8 is selected from H, or the following groups which are unsubstituted or optionally substituted with one or more Rb: C1-40 alkyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, NRdRe, —CONRdRe, —C(O)Y2Rf, —Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3;
R9 is selected from the following groups which are unsubstituted or optionally substituted with one or more Rb: R10—Y3—Y4—, R11—C(O)—Y5—Y6—, C1-40 alkyl, C1-40 alkoxy, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, —Y2—N(R4)—C(═NH)—NH2, —Y3—N(R2)—C(O)—Y2—N(R4)—C(═NH)—NH2, —(CH2CH2O)z—H, wherein z is an integer of 1 or more, preferably an integer of 1 to 10;
R10 and R11 are independently selected from H, or the following groups which are unsubstituted or optionally substituted with one or more Rb: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
Y1, Y2, Y3, Y4, Y5, and Y6 are independently selected from a chemical bond, —O—, —S— or the following groups which are unsubstituted or optionally substituted with one or more Ra: —NH—, C1-40 alkyl, C1-40 alkoxy, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, or —(CH2CH2O)m, wherein m is an integer of 0 or more, for example, an integer from 0 to 10.
Preferably, when two or more of Y1, Y2, Y3, Y4, Y5 or Y6 are adjacent, the adjacent groups are not chemical bonds at the same time;
Each Ra is independently selected from H, C1-40 alkyl, C1-40 alkoxy, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, F, Cl, Br, I, OH, SH, CN, ═O, NRdRe, —C(O)Y2Rf, —Y2(O)CRf, —CONRdRe, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
Each Rb is independently selected from H, F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted with one or more Ra: C1-40 alkyl, C1-40 alkoxy, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, C3-20 cycloalkyloxy, 3-20 membered heterocyclyl, 3-20 membered heterocyclyloxy, C6-20 aryl, C6-20 aryloxy, 5-20 membered heteroaryl, 5-20 membered heteroaryloxy, NRdRe, —CONRdRe, —C(O)Y2Rf, —Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
Each Rc is independently selected from F, Cl, Br, I, OH, SH, CN or the following groups which are unsubstituted or optionally substituted with one or more Ra: C1-40 alkyl, C1-40 alkoxy, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, NRdRe, —CONRdRe, —C(O)Y2Rf, —Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
Each Rd and Re are independently selected from H, or the following groups which are unsubstituted or optionally substituted with one or more Rm: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, —CONRfRg, —C(O)Y2Rf, —Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3;
Each Rf and Rg are independently selected from H, or the following groups which are unsubstituted or optionally substituted with one or more Rm: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, COOH, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl.
Each Rm is independently selected from H, F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted with one or more Ra: C1-40 alkyl, C1-40 alkoxy, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, NRdRe, —CONRdRe, —C(O)Y2Rf, Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
M1, M2, and M3 are independently selected from H, or C1-40 alkyl which is unsubstituted or optionally substituted with one or more Rb.
Provided that when R is
R1 is not hydroxyl; and when Rt is
R3 is not —CH2NHCH3;
wherein the heterocyclyl and heteroaryl independently from each other contain 1-5 heteroatoms independently selected from N, O, or S.
According to an embodiment of the present disclosure, wherein:
X1 and X2 are independently from each other selected from F, Cl, or Br;
X3 can represent an acid ion generated by ionization of an inorganic acid or an organic acid;
The number of acid ions represented by X3 is not particularly limited, for example, X3 can represent a monovalent acid ion generated by ionization of an inorganic or organic acid;
Alternatively, when a plurality of cations are present in the structure of the compound of formula (I), X3 can represent a plurality of monovalent acid ions generated by ionization of an inorganic acid or an organic acid, preferably 2 or 3 monovalent acid ions generated by ionization of an inorganic acid or an organic acid;
Alternatively, when a plurality of cations in the structure of the compound of formula (I) share one polyvalent acid ion, X3 can also represent a part of the polyvalent acid ion, for example, ½, ⅓, ⅔ of the polyvalent acid ion;
Persons skilled in the art should understand that when there are multiple sulfonium ions in the compound of formula (I), X3 can also represent a mixture of the monovalent acid ions, a mixture of the polyvalent acid ions, or a mixture of the monovalent acid ions and the polyvalent acid ions.
For example, X3 can represent Cl−, Br−, I−, HSO4−, NO3−, ½SO42−, SO42−, 3/2SO42−, H2PO4−, ½HPO42−, 3/2HPO42−, ⅓PO43−, ⅔PO43−, or PO43−;
R2 is selected from H, or C1-40 alkyl (for example, methyl, ethyl, propyl, isopropyl, or tert-butyl) which is unsubstituted or optionally substituted with one or more Ra;
R3 is selected from C1-40 alkyl which is unsubstituted or optionally substituted with one or more Rb; for example, R3 can be C1-40 alkyl substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, —NH2, —COOH, —OH, —CONH2, N(CH3)2, NH(CH3), NHCONH2, (C6H4)—OH, or NH(CH2)kCH3;
As an example, R3 can be —(CH2)k—NH2, —CH(NH2)—(CH2)k—COOH, NH2(CH2)kCH(NH2), CH2CH(NH2)COOH, —(CH2)k—COOH, —CH(NH2)—(CH2)k—NH—CONH2, CH(NH2)—(CH2)k—CONH2, —CH(NH2)—(CH2)k—OH, —CH(NH2)—(CH2)k—CH(OH)—CH3, —CH(NH2)—(CH2)k—(C6H4)—OH, —CH(NH2)—(CH2)k—NH—(CH2)k—CH3, —(CH2)k—NH—(CH2)k—CH3, —(CH2)k—N(CH3)2, wherein k is independently selected from an integer of 0 to 16, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10;
Ar can be selected from the following groups which are unsubstituted or optionally substituted with one or more Rc: C6-10 aryl, 5-10 membered heteroaryl;
For example, Ar can be selected from pyridyl, phenyl, specifically
wherein the C atom at 2-position of the pyridyl is connected to N atom, and the C atom at 3-position is connected to methylene group.
According to an embodiment of the present disclosure, R can be selected from

R3a can be selected from C1-40 alkyl which is unsubstituted or optionally substituted with one or more NRdRe.
According to the present disclosure, the group that can be converted into a hydroxyl group in vivo can be an ester group that can be converted into a hydroxyl group in vivo, for example, an ester group that can be converted into a hydroxyl group in vivo by hydrolysis and/or enzymatic hydrolysis. The ester groups include polyether ester group, phosphate group, sulfate group, heterocyclic ester group, alkanoate group, alkenoate group, amino acid ester group, carbonate group, or acid ester group. As an example, the ester group can be phosphate group, amino acid ester group, carbonate group or acidic ester group.
The ester group can be structurally represented as a group produced by removing a group linked to an oxy group in the ester functional group, for example, a group represented by the following formula (H1) or (H2):

wherein p, q, and r are independently selected from 0 or 1;
Y1 is selected from chemical bond or —O—;
Y2 is selected from chemical bond, —O—, —S— or —NH— unsubstituted or optionally substituted with one or more Ra;
E1 is selected from chemical bond, or C1-40 alkyl which is unsubstituted or optionally substituted with one or more Rc;
E2 is independently selected from chemical bond or —OC(O)—;
E3 is independently selected from chemical bond, or the following groups which are unsubstituted or optionally substituted with one or more Rc: C1-40 alkyl, C2-40 alkenyl, C2-40 alkynyl, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, or 5-20 membered heteroaryl; preferably from C1-40 alkyl, C6-20 aryl, C6-20 arylalkyl, or 5-20 membered heteroaryl which are unsubstituted or independently substituted with one or more Rc, for example, —(CH2)k—, —(CH2)k—(C6H4)—, —(CH2CH2O)z—, wherein k is an integer selected from 0 to 10; z is an integer of 1 or more, preferably an integer of 1 to 10;
Provided that E1 and E3 are not chemical bonds at the same time;
E4 and E5 are independently from each other selected from H, and the following groups which are unsubstituted or optionally substituted with one or more Rc: C1-40 alkyl, 3-20 membered heterocyclyl, C6-20 aryl, or 5-20 membered heteroaryl;
Rc has the definition as described above.
As an example, the phosphate group according to the present disclosure can be, for example, a phosphate group represented by the following formula:

wherein p has the definition as described above;
Each Rj is independently selected from H, OH, and C1-40 alkyl which is unsubstituted or optionally substituted with one or more Ra, preferably OH;
t is an integer selected from 1 to 6, preferably 2 or 3;
n and j are independently selected from an integer of 0 to 4;
m is selected from 0 or 1;
Each W is independently selected from H, benzyl or

As an example, the phosphate group can be selected from
n is an integer selected from 0 to 5.
For example, R1 can be
wherein n is 1, 2, or 3; as an example, when R is
R1 is
wherein n is 1.
The amino acid ester group of the present disclosure can be selected from amino acid ester groups, dipeptide ester group or polypeptide ester group, including but not limited to:
natural (L)-α-amino acid ester groups, such as glycine ester group (—OCOCH2NH2), L-alanine ester group, L-phenylalanine ester group, glycine ester group, L-leucine ester group, L-serine ester group, L-isoleucine ester group, L-valine ester group, L-glutamine ester group, L-asparagine ester group, L-threonine ester group, methyl glycine ester group, ornithine ester group, L-isoleucine ester group, and L-valine ester group;
Non-natural α-amino acid ester groups, such as —OC(O)CH(NH2)(CH2)3CO2H, —OC(O)CH(NH2)(CH2)2NH2, —OC(O)CH(NH2)(CH2)3NH2, or an α-aminoalkanoate group represented by the formula —OC(O)CH(NR22R23)R24;
R22 and R23 is independently selected from H or C1-40 alkyl which is unsubstituted or optionally substituted with one or more Ra, or alternatively R22 and R23 together with N can form 3-20 membered heterocyclyl or 5-20 membered heteroaryl which optionally contain O or S as a ring-forming atom, for example, 4-, 5-, or 6-membered heterocyclyl or heteroaryl;
R24 is H or C1-40 alkyl which is unsubstituted or optionally substituted with one or more Rc;
Each Rc independently has the definition as described above; as an example, each Rc is independently selected from CH3, —OH, —CH2OH, —CONH2, —CH2CONH2, —(CH2)2CONH2, —CH(CH3)2, —C(CH3)3, —CH(CH3)C2H5, —COOH, —CH2CO2H, —(CH2)2CO2H, —C6H5, or —CH2C6H5.
Preferred amino acid ester groups are ester groups derived from the following natural a-amino acids: L-alanine, L-phenylalanine, glycine, L-leucine, L-serine, L-glutamine, L-asparagine, L-threonine, methylglycine, ornithine, L-isoleucine, and L-valine. Further preferred amino acid ester groups are glycine ester group —OCOCH2NH2, serine ester group —OCOCH(NH2)CH2OH, threonyl ester group —OCOCH(NH2)CH(OH)CH3, leucine ester group —OCOCH(NH2)CH2CH(CH3)2, isoleucyl ester group —OCOCH(NH2)CH(CH3)CH2CH3, orvaline ester group —OCOCH(NH2)CH(CH3)2.
The acidic ester groups described herein can be selected from acidic ester groups represented by the following formula
wherein R21 is independently selected from H, OH, C1-40 alkyl which is unsubstituted or optionally substituted with one or more Ra, preferably OH, and k has the definition as described above.
Preferred acidic ester groups include oxalate group, malonate group, succinate group, glutarate group and adipate group, and branched diacid ester groups, such as ester groups of

The alkanoate groups described herein can be selected from alkanoate groups that are unsubstituted or optionally substituted with hydroxy and/or ether group. Preferred alkanoate groups include C2-12 alkanoate groups, such as C2-4 alkanoate groups, that are unsubstituted or optionally substituted by hydroxy and/or ether group. As an example, the alkanoate group can be C1-C8 alkanoate group substituted with one hydroxy group and/or one C1-6 alkoxy group.
The alkenoate groups described herein can be selected from alkenoate groups that are unsubstituted or optionally substituted with hydroxy and/or ether group. Preferred alkenoate group can be C10-20 alkenoate group, including C14-18 alkenoate group, such as cis-7-hexadecenoate group.
The carbonate groups described herein can be selected from unsubstituted or substituted alkoxycarbonyloxy groups, for example
as defined above.
According to an embodiment of the present disclosure, Rh can be selected from, for example,
—O(O)CRf, —OP(O)(OM1)(OM2), —OS(O)2OM3, or C1-40 alkoxy which is unsubstituted or optionally substituted with one or more Rb;
According to an embodiment of the present disclosure, Rh can be selected from, for example,
preferably, when R is
Rh is

wherein, R1a can be selected from C1-40 alkyl, C6-20 aryl, C6-20 arylalkyl, 5-20 membered heteroarylalkyl, and 5-20 membered heteroaryl which are unsubstituted or optionally substituted with one or more C(O)ORf, —OP(O)(OM1)(OM2), —OS(O)2OM3; preferably, R1a is selected from —(CH2)k—C(O)ORf, —(CH2)k—(C6H4)—C(O)ORf, —(CH2)z—OP(O)(OM1)(OM2), —(CH2)k—(C6H4)—OP(O)(OM1)(OM2), —(CH2)k—(C6H4)—OS(O)2OM3, —(CH2)z—S(O)2OM3 k is an integer of 0-10; z and Rf have definitions as described above;
R1b can be selected from H or C1-40 alkyl, for example H, methyl, ethyl, or isopropyl;
R9 is selected from the following groups which are unsubstituted or optionally substituted with one or more Rb: R10—Y3—Y4—, R11—C(O)—Y5—Y6—, C1-40 alkyl, C1-40 alkoxy, —Y2—N(R4)—C(═NH)—NH2, —Y3—N(R2)—C(O)—Y2—N(R4)—C(═NH)—NH2, —(CH2CH2O)z—H, wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
R10 and R11 have the definitions as described above and can be, for example

Rf is selected from the following groups which are unsubstituted or optionally substituted with one or more Rm: C1-40 alkyl, COOH, 3-20 membered heterocyclyl, C6-20 aryl, or 5-20 membered heteroaryl;
Each Rm is independently selected from H, F, Cl, Br, I, OH, SH, CN, or the following groups which are unsubstituted or optionally substituted with one or more Ra: C1-40 alkyl, C1-40 alkoxy, C3-20 cycloalkyl, 3-20 membered heterocyclyl, C6-20 aryl, 5-20 membered heteroaryl, NRdRe, —CONRdRe, C(O)Y2Rf, Y2(O)CRf, —Y2P(O)(OM1)(OM2), or —Y2S(O)2OM3.
M1, M2, and M3 can be selected from H, methyl, ethyl, or isopropyl.
As an example, Rh can be selected from —OP(O)(OH)2, —OS(O)2OH, —OC(O)CH(OH)CH(OH)CH2OP(O)(OH)2, —OC(O)CH(NH2)CH2OH, —OC(O)OCH(CH3)OC(O)CH2CH2COOH, —OC(O)OCH(CH3)OC(O)CH2COOH, —OC(O)OCH(CH3)OC(O)COOH, —OC(O)OCH(CH3)OC(O)C6H4COOH, —OC(O)OCH(CH3)OC6H3(COOH)2, —OC(O)OCH(CH3)OC(O)CH2CH2CH3, —OC(O)OCH(CH3)OC(O)CH2NH2, —OC(O)OCH(CH3)OC(O)CH2NHCH3, —OC(O)OCH(CH3)OC(O)CH2N(CH3)P(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2NHP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2N(CH3)S(O)2OH, —OC(O)OCH(CH3)OC(O)CH2NHS(O)2OH, —OC(O)OCH(CH3)OC(O)CH2N(CH3)2, —OC(O)OCH2CH2OP(O)(OH)2, —OC(O)O(CH2CH2O)2P(O)(OH)2, —OC(O)O—(CH2CH2O)3—P(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)C6H5OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2C6H5OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2C6H5OS(O)2OH, —OC(O)OCH(CH3)OC(O)CH2NHC(═NH)NHP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2N(CH3)C(═NH)NHP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2NHC(O)CH2N(CH3)C(═NH)NHP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2N(CH3)CH2OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2N(CH3)C(O)CH2OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH2NHC(O)CH2OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)CH(OH)CH2OP(O)(OH)2, —OC(O)OCH[(CH2)3OS(O)2OH]OC(O)CH2N(CH3)2, —OC(O)OCH[(CH2)3OS(O)2OH]OC(O)CH2NHCH3, OC(O)OCH[(CH2)3OP(O)(OH)2]OC(O)CH2N(CH3)2, —OCH(C2H5)OP(O)(OH)2, —OCH(C6H5)OP(O)(OH)2, —OC(O)OCH(CH3)OC(O)—[CH(OH)]4—CH2OH, —OC(O)OCH(CH3)OC(O)CH(COOH)2,
—OC(O)OCH(CH3)OC(O)(CH2)kOP(O)(OH)2, —OC(O)OCH2OC(O)(CH2)kOP(O)(OH)2, —OC(O)OCH(CH3)OC(O)(CH2)kOS(O)2OH, —OC(O)OCH2OC(O)(CH2)kOS(O)2OH, wherein each k independently has the definition as described above;
According to an embodiment of the present disclosure, the pharmaceutically acceptable salts of the compounds of formula (I) includes, but is not limited to:
alkali metal salts, alkaline earth metal salts, ammonium salts of compounds of formula (I), or salts of compounds of formula (I) formed with organic bases providing physiologically acceptable cations, for example salts of compounds of formula (I) formed with sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glycosamine, meglumine, sarcosine, serinol, trishydroxymethyl aminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, when 1, 2, or 3 of M1, M2, and M3 is/are H, the pharmaceutically acceptable salts include, for example, the pharmaceutically acceptable salts of the present disclosure include, for example, salts formed from —OP(O)(OM1)(OM2), —P(O)(OM1)(OM2), —OS(O)2OM3, or —S(O)2OM3, with, for example, the above-mentioned sodium ion, potassium ion, ammonium ion, and the like;
or alternatively,
acid addition salts of compounds of formula (I) with the following acids: inorganic acids such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxyl benzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, embonic acid, pectinic acid, persulfuric acid, 3-phenyl propionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.
Persons skilled in the art should understand that, if appropriate, the pharmaceutically acid addition salts of the compound of formula (I) include not only salts formed by 1 molecule of the compound of formula (I) with 1 molecule of acid, but also salts formed by several molecules of compound of formula (I) with 1 molecule of acid (e.g. hemisulfate), salts formed by 1 molecule of compound of formula (I) with several molecules of acid, and salts formed by several molecules of compound of formula (I) with several molecules of acid. Also, if appropriate, alkali metal salts, alkaline earth metal salts, ammonium salts of compounds of formula (I), or salts of compounds of formula (I) with organic bases that provide physiologically acceptable cations include not only salts formed by 1 molecule of compound of formula (I) with 1 cation, but also salts formed by several molecules of compound of formula (I) with 1 cation, and salts formed by 1 molecule of compound of formula (I) with several cations.
According to a preferred embodiment of the present disclosure, the compound of formula (I) can have the structure represented by the following formula (I′):

wherein, each group has the definition as described above.
As an example, the compound of formula (I) can be selected from the following compounds and pharmaceutically acceptable salts thereof:
No.Structure0001 0002 0003 0004 0005 0006 0007 0008 0009 0010 0011 0012 0013 0014 0015 0016 0017 0018 0019 0020 0021 0022 0023 0024 0025 0026 0027 0028 0029 0030 0031 0032 0033 0034 0035 0036 0037 0038 0039 0040 0041 0042 0043 0044 0045 0046 0047 0048 0049 0050 0051 0052 0053 0054 0055 0056 0057 0058 0059 0060 0061 0062 0063 0064 0065 0066 0067 0068 0069 0070 0071 0072 0073 0074 0075 0076 0077 0078 0079 0080 0081 0082 0083 0084 0085 0086 0087 0088 0089 0090 0091 0092 0093 0094 0095 0096 0097 0098 0099 0100
The pharmaceutically acceptable salts of the above compounds can be an acidic salt or a basic salt. For example, the salts can be hydrochloride, sulfate, nitrate, phosphate, or salts formed by the compounds with sodium ion, potassium ion, ammonium ion, or the like. Specifically, the salts can be listed as follows.
No.Structure formulaST0001 ST0002 ST0003 ST0004 ST0005 ST0006 ST0007 ST0008 ST0009 ST0010 ST0011 ST0012 ST0013 ST0014 ST0015 ST0016 ST0017 ST0018 ST0019 ST0020 ST0021 ST0022 ST0023 ST0024 ST0025 ST0026 ST0027 ST0028 ST0029 ST0030 ST0031 ST0032 ST0033 ST0034 ST0037 ST0038 ST0039 ST0040 ST0041 ST0042 ST0043 ST0044 ST0045 ST0046 ST0047 ST0048 ST0049 ST0050 ST0052 ST0053 ST0054 ST0055 ST0056 ST0057 ST0058 ST0059 ST0060 ST0061 ST0062 ST0063 ST0064 ST0065 ST0066 ST0067 ST0068 ST0069 ST0070 ST0071 ST0072 ST0073 ST0074 ST0075 ST0076 ST0077 ST0078 ST0079 ST0080 ST0081 ST0082 ST0083 ST0084 ST0085 ST0086 ST0087 ST0088 ST0089 ST0090 ST0091 ST0092 ST0093 ST0094 ST0095 ST0100 ST0101 ST0102 ST0103 ST0104 ST0105 ST0106
The present disclosure also provides a method for preparing the compound of the formula (I), which comprises preparing the compound of the formula (I) by using the compound represented by the following formula (II) as a raw material:

wherein, X1 and X2 have the definitions as described above.
According to an embodiment of the present disclosure, for example, the compound of the above formula (I′) can be prepared by using the compound represented by the following formula (II′) as a raw material:

wherein, X1 and X2 have the definitions as described above.
According to the preparation method of the present disclosure, persons skilled in the art can select appropriate raw materials to react with the compound of formula (II) to obtain the compound of formula (I). For example, a suitable raw material can be selected to react with a compound of formula (II′) to provide a compound of formula (I′).
According to an embodiment of the present disclosure, the preparation method can include, for example, reacting a compound of formula (II) with a compound Rz-L, wherein Rz is selected from Rh, Rt or a group which can be derivatized as Rh or Rt, wherein Rh and Rt have the definitions as described above, and L is a leaving group. For example, Rz-L can be selected from Rh-L1 or Rt-L2, wherein Rh and Rt have the definitions as described above, and L1 and L2 are selected from leaving groups.
According to an embodiment of the present disclosure, the preparation method can be carried out in the presence of a catalyst.
According to an embodiment of the present disclosure, the preparation method can be carried out in the absence of a solvent or in the presence of a solvent.
If desired, the compound of formula (II) can be first reacted with Rh-L1 and the resulting compound can be further reacted with Rt-L2;
Alternatively, the compound of formula (II) is first reacted with Rt-L2 and the resulting compound can be further reacted with Rh-L1.
If desired, one or more functional groups in the compound of formula (II) and/or compound Rz-L can be first protected with a protecting group (PG) and then subjected to the reaction. The functional group can be selected from, for example, one or more of amino group, amine group, hydroxyl group, mercapto group, carboxyl group, carbon-carbon double bond, and carbon-carbon triple bond. Each of the protecting groups (PG) can be selected from, for example, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), allyloxycarbonyl, trimethylsilyloxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (pht), p-toluenesulfonyl (Ts), trifluoroacetyl (Tfa), pivaloyl, benzoyl, trityl (Trt), 2,4-dimethoxybenzyl (Dmb), p-methoxybenzyl (PMB), benzyl (Bn), tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triisopropylsilyl (TIPS—OR), tert-butyl (t-Bu).
If necessary, after the completion of the reaction, the protecting group can be removed for subsequent reactions or to obtain the target compound.
According to the present disclosure, when Rz is selected from a group that can be derivatized as Rh or Rt, Rz represents a group that can be further reacted to give Rh or Rt.
According to the present disclosure, preferably, the compound represented by the formula (II) or (II′) as the substrate does not undergo a configuration conversion during the reaction.
As an illustrative example, the preparation method includes, but is not limited to, at least one of the following reactions:

Preferably,

wherein, R′ represents

R4, Rh, X1, X2, X3, Y3, Y4, and PG have the definitions as described above.
X3′ represents an organic substituent that can be converted to X3;
L3 and L4 independently from each other are selected from leaving groups such as F, Cl, Br, or I;
Preferably, the reaction, for example the reaction 4) can be carried out in the presence of a catalyst such as NaBr, NaI or a mixture thereof.
The present disclosure also provides a method for preparing the compound Rt—X3′, including but not limited to one or more of the following reactions:

wherein, each substituent has the definition as described above;
Preferably, the method for preparing the compound Rt—X3 is carried out in the presence of a base or a condensing agent.
The present disclosure also provides a compound represented by formula (VII):

wherein, R2, R3, R4, X3, and Ar have the definitions as described above.
The present disclosure also provides the use of the compound of formula (VII) in the preparation of a posaconazole derivative such as the compound of formula (I).
The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present disclosure (including the compound represented by formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof). The pharmaceutical composition can also optionally contain a pharmaceutically acceptable adjuvant such as a carrier, an excipient. As an example, the adjuvant can be one or more selected from disintegrants, glidants, lubricants, diluents or fillers, binders, colorants.
The present disclosure also provide use of a compound of the present disclosure including a compound represented by formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof in the preparation of an antibiotic drug, in particular an antifungal (including but not limited to Candida albicans, Aspergillus fumigatus) drug.
The present disclosure also provide use of a compound of the present disclosure including a compound represented by formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof in the prevention or treatment of a disease. The disease is, for example, caused by a fungus (including but not limited to Candida albicans, Aspergillus fumigatus).
Definition and Explanation of Terms
Unless otherwise indicated, the definitions of groups and terms in the specification and claims of this application include definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, and the like which can be in any combination or association with each other. Such combined and associated group definitions and compound structures should fall within the scope of the description of the present application.
Whenever a numerical range recited in the specification and claims herein is defined as “an integer”, it should be understood that both endpoints of the range and each integer within the range are recited. For example, “an integer of 0 to 10” or “an integer selected from 0 to 10” should be understood as describing each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. When the numerical range is defined as “a number”, it should be understood that both endpoints of the range, each integer within the range, and each decimal within the range are recited. For example, “a number from 0 to 10” should be understood to include not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of the integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.
Unless otherwise indicated, when “a compound of the present disclosure” or “a compound according to the present disclosure” is used herein, it is intended to encompass a compound represented by Formula (I), a racemate, stereoisomer, tautomer, oxynitride, or a pharmaceutically acceptable salt thereof.
The term “halogen” refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as “halogen” in this specification.
“Optionally substituted with” or “optionally substituted” means being substituted with a group selected from the substituents.
The term “C1-40 alkyl” is understood to preferably denote a straight or branched saturated monovalent hydrocarbon group having 1 to 40 carbon atoms, preferably a C1-10 alkyl group. “C1-10 alkyl” is understood to preferably denote a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, iso-amyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, and the like or their isomers. In particular, the groups have 1, 2, 3, 4, 5, or 6 carbon atoms (“C1-6 alkyl”) such as methyl, ethyl, propyl, butyl, isopropyl, iso-butyl, sec-butyl, tert-butyl. More particularly, the groups have 1, 2 or 3 carbon atoms (“C1-3 alkyl”) such as methyl, ethyl, n-propyl or isopropyl.
The term “C2-40 alkenyl” is understood to preferably denote a straight-chain or branched monovalent hydrocarbon group containing one or more double bonds and having 2 to 40 carbon atoms, preferably “C2-10 alkenyl”. “C2-10 alkenyl” is understood to preferably denote a straight or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, particularly 2 or 3 carbon atoms (“C2-3 alkenyl”). It is to be understood that where the alkenyl group contains more than one double bond, the double bonds can be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hexa-2-alkenyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-ene (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, and 1-isopropylvinyl.
The term “C2-40 alkynyl” is understood to denote a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2 to 40 carbon atoms, preferably “C2-C10 alkynyl”. The term “C2-C10 alkynyl” is understood to preferably denote a straight or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, especially 2 or 3 carbon atoms (“C2-C3 alkynyl”). The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, penta-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbutane-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpentyl-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbutyl-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term “C3-20 cycloalkyl” is understood to denote a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably “C3-10 cycloalkyl”. The term “C3-10 cycloalkyl” is understood to denote a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C3-10 cycloalkyl group can be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl, or a bicyclic hydrocarbon group such as decahydronaphthalene cyclyl.
The term “C5-20 cycloalkenyl” is understood to denote a conjugated or non-conjugated monovalent monocyclic or bicyclic hydrocarbon ring having an unsaturation of 1, 2 or 3 and having 5 to 20 carbon atoms, preferably “C5-10 cycloalkenyl”. The term “C5-10 cycloalkenyl” is understood to denote an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring having 5, 6, 7, 8, 9 or 10 carbon atoms. The C5-10 cycloalkenyl group can be a monocyclic hydrocarbon group such as 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 2,4-cyclopentadienyl, 2,5-cyclohexadienyl or 1,3,5-cycloheptatrienyl or 1,3,6-cycloheptatrienyl, or a bicyclic hydrocarbon such as hexahydronaphthalene cyclyl, and octahydronaphthalene cyclyl. Unless otherwise indicated, the term “C5-20 cycloalkenyl” includes all possible isomeric forms thereof, such as positional isomers or configurational isomers thereof.
The term “3-20 membered heterocyclyl” denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably “3-10 membered heterocyclyl”. The term “3-10 membered heterocyclyl” denotes a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms selected from N, O and S. The heterocyclyl group can be attached to the rest of the molecule through any one of the carbon atoms, or if present, a nitrogen atom. In particular, the heterocyclyl can include, but is not limited to, 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithiyl; or 7-membered ring, such as diazepanyl. Optionally, the heterocyclyl can be benzo-fused. The heterocyclyl can be bicyclic, such as but not limited to a 5,5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The nitrogen-containing ring can be partially unsaturated, i.e., it can contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, alternatively, it can be benzo-fused, such as but not limited to dihydroisoquinolyl. According to the present disclosure, the heterocyclyl is not aromatic.
The term “C6-20 aryl” is understood to preferably denote a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C6-14 aryl”. The term “C6-14 aryl” is understood to preferably denote a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (“C6-14 aryl”), especially a ring having 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring having 9 carbon atoms (“C9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms (“C13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C14 aryl”), such as fluorenyl.
The term “5-20 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, such as “5-14 membered heteroaryl”. The term “5-14 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and containing 1-5, preferably 1-3, heteroatoms independently selected from N, O and S, and in addition, can be benzo-fused in each case. In particular, the heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thio-4H-pyrazolyl, the like and their benzo derivatives, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof such as quinolyl, quinazolinyl, isoquinolinyl, and the like; or azocinyl, indolizinyl, purinyl, the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridine, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like.
Unless otherwise indicated, heterocyclyl, heteroaryl, or heteroarylene includes all possible isomeric forms thereof, such as its positional isomers. Thus, for some illustrative non-limiting examples, pyridyl or pyridylene group includes pyridin-2-yl, pyridylen-2-yl, pyridin-3-yl, pyridylen-3-yl, pyridin-4-yl, and pyridylen-4-yl; thienyl or thienylene group include thiophen-2-yl, thienylen-2-yl, thiophen-3-yl, and thienylen-3-yl.
The triazolyl in the present disclosure includes 1,2,3-triazolyl, 1,2,4-triazolyl or 1,3,5-triazolyl.
The above definition of the term “alkyl”, such as “C1-40 alkyl” applies equally to other terms containing “C1-40 alkyl” such as the term “C1-40 alkyloxy” or “C1-40 alkoxy”, “C1-40 alkylsilyl” and “C1-40 alkylsilyloxy” and the like. Similarly, the above definitions of the terms “C2-40 alkenyl”, “C2-40 alkynyl”, “C3-20 cycloalkyl”, “C5-20 cycloalkenyl”, “3-20 membered heterocyclyl”, “C6-20 aryl” and “5-20 membered heteroaryl” apply equally to other terms containing the same, such as the terms “C2-40 alkenyloxy”, “C2-40 alkynyloxy”, “C3-20 cycloalkyloxy”, “3-20 membered heterocyclyloxy”, “C6-20 aryloxy”, “C6-20 arylalkyl” and “5-20 membered heteroarylalkyl” and the like.
Unless otherwise indicated, the term “leaving group” as used herein denotes a charged or uncharged atom or group that disassociates during a substitution or displacement reaction. Suitable examples include, but are not limited to, H, F, Br, Cl, I, mesylate ester group, tosylate ester group, and the like.
In any method for preparing the compounds of the present disclosure, it can be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be achieved by conventional protecting groups, such as those described in textbooks or reference books in the field. The protecting groups can be removed at a convenient subsequent stage using methods known in the art. Persons skilled in the art will recognize that depending on the particular protecting group, other reagents, including but not limited to Pd/C, Pd(OH)2, PdCl2, Pd(OAc)2/Et3SiH, Raney nickel, appropriately selected acids, appropriately selected bases, fluorides, and the like can be used for the step of removing the protecting groups.
The target compound can be isolated according to a known method, for example, by extraction, filtration or column chromatography.
According to its molecular structure, the compounds of the present disclosure can be chiral and thus can exist in various enantiomeric forms. Thus, these compounds can exist in the form of racemates or optically active forms. The compounds of the present disclosure or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to persons skilled in the art or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) in R and S forms or various optically active camphorsulfonic acids. With the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous-containing or alcohol-containing solvent mixtures, for example, hexane/isopropanol/acetonitrile.
Persons skilled in the art will understand that since nitrogen needs to have available lone pairs of electrons for oxidation to oxides, not all nitrogen-containing heterocycles can form N-oxides; persons skilled in the art will identify nitrogen-containing heterocycles capable of forming N-oxides. Persons skilled in the art will also recognize that tertiary amines can form N-oxides. Methods for synthesizing N-oxides of heterocyclic and tertiary amines are well known to persons skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethylbisoxirane oxidized heterocycle and tertiary amines. These methods for preparing N-oxides have been extensively described and reviewed in the prior art.
Pharmaceutically acceptable salts can be, for example, acid addition salts of the compounds of the present disclosure having a sufficiently basic nitrogen atom in the chain or ring, for example, acid addition salts formed with the following inorganic acids: such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrosulfate; or acid addition salts formed with the following organic acids: formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxyl) benzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, embonic acid, pectinic acid, persulfuric acid, 3-phenyl propionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanate acid.
In addition, another suitable pharmaceutically acceptable salt of the compound of the present disclosure having sufficient acidity is alkali metal salt (e.g., sodium salt or potassium salt), alkaline earth metal salt (e.g., calcium salt or magnesium salt), ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation, such as a salt formed with: sodium ion, potassium ion, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, lysine, dicyclohexylamine, 1,6-hexamethylenediamine, ethanolamine, glycosamine, meglumine, sarcosine, serinol, trishydroxymethyl aminomethane, aminopropylene glycol, 1-amino-2,3,4-butanetriol. As an example, when 1, 2, or 3 of M1, M2, and M3 is/are H, the pharmaceutically acceptable salt includes, for example, salts formed from —OP(O)(OM1)(OM2), —P(O)(OM1)(OM2), —OS(O)2OM3, and —S(O)2OM3, with, for example, above-mentioned sodium ion, potassium ion, ammonium ion, and the like;
In addition, basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long-chain halides such as chloride, bromide and iodide of decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; aralkyl halides such as benzyl and phenylethyl bromide, and the like. As an example, pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, mesylate, formate or meglumine salt and the like.
Since the compounds of the present disclosure can have a plurality of salt-forming sites, the “pharmaceutically acceptable salts” include not only the salts formed on one salt-forming site of the compound of the present disclosure but also the salts formed on 2, 3 or all salt formation sites. Therefore, the molar ratio of the compound of formula (I) and the acid ion (anion) or cation of the base required for forming the salt in the “pharmaceutically acceptable salt” can vary within a relatively large range, for example, 4:1-1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, and so on.
According to the present disclosure, pharmaceutically acceptable anions include acid ions selected from those ionized by inorganic or organic acids. The “inorganic acid” includes but is not limited to hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid. The “organic acid” includes but is not limited to formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxyl) benzoyl) benzoic acid, camphoric acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, embonic acid, pectinic acid, persulfuric acid, 3-phenyl propionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, gluconic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanate.
The term “acid ion generated by ionization” encompasses all forms of acid ions that can be generated by ionization of the inorganic and organic acids, for example, different acid ions can be generated through primary ionization, secondary ionization, or tertiary ionization. As an example, phosphoric acid can generate dihydrogen phosphate by primary ionization, can generate hydrogen phosphate by secondary ionization, and can generate phosphate by tertiary ionization; sulfuric acid can generate hydrogen sulfate by primary ionization, and can generate sulfate by secondary ionization of sulfate. In the compound of the formula (I) of the present disclosure, a plurality of molecules can share one multivalent anion generated by multiple levels of ionization. All these possible generated acid ions are covered by the acid ions or anions described in the present disclosure.
The term “tautomer” refers to a functional isomer resulting from the rapid movement of an atom in a molecule at two positions. The compounds of the present disclosure can exhibit tautomerism. Tautomeric compounds can exist in two or more mutually convertible species. Prototropic tautomers result from the transfer of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium and attempts to isolate a single tautomer often produce a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; in phenols, the enol type predominates. The present disclosure includes all tautomeric forms of the compounds.
The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound of the present disclosure that is sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The therapeutically effective amount can vary depending on such factors as the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the manner of administration, etc., which can be easily determined by persons skilled in the art. The specific dose will vary depending on the particular compound selected, the dosing regimen upon which it is administered, whether it is to be administered in combination with other compounds, the timing of dosing, the tissue to be administered and the physical delivery system carried.
The term “adjuvant” refers to pharmaceutically acceptable inert ingredients. Examples of types of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., the formulation is more suitable for direct compression by increasing fluidity and/or tackiness. Examples of typical pharmaceutically acceptable carriers suitable for use in the above formulations are: saccharides such as lactose, sucrose, mannitol and sorbitol; starch types such as corn starch, tapioca starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil; nonionic, cationic and anionic surfactants; ethylene glycol polymers; fatty alcohols; and cereals hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, colorants, etc. commonly used as excipients in pharmaceutical formulations.